To investigate the basis of apathogenic infection in sooty mangabeys, three sooty mangabeys and three rhesus macaques were concurrently inoculated with SIVmac239 via the intravenous route and monitored for one year. Vigorous and polyclonal SIV-specific CTL activity coincident with a decline in peak plasma viremia was detected during the acute phase of infection in all the animals. Eight to 20 weeks after SIV infection, SIV-specific CTL activity was absent or low in the macaques, while it was sustained and broad in the sooty mangabeys. These differences were associated with 2 to 4 log higher plasma viral RNA levels in the macaques. Peripheral T cell homeostasis and percentages of CD4+ and CD8+ T lymphocytes were maintained in 3/3 mangabeys. In contrast, 3/3 macaques developed progressive CD4+ T lymphocytopenia, 2 to 16 weeks following SIV infection. T cell homeostasis was maintained in only 1/3 macaques. Memory CD45RA- peripheral T lymphocytes were markedly reduced in 2/2 rhesus macaques, but preserved and increased in 2/2 sooty mangabeys during SIV infection. Significant differences in the percentage of circulating naive CD45RA+ CD62L-selectin+ T lymphocytes were not observed. Striking differences were observed when unstimulated peripheral blood mononuclear cells in one sooty mangabey and one macaque were assessed for intracellular cytokine secretion by flow cytometry during acute SIV infection. From day 7 onwards, increased secretion of IL-2 and interferon-gamma was observed in the rhesus macaque, while only IL-10 secretion was evident in the sooty mangabey. Differences in host responses to SIV may contribute to the divergent outcome of infection in sooty mangabeys and rhesus macaques, and identification of these divergent responses may yield information useful to the design of immune-based therapies for AIDS.